Molecular Characterization of an Interleukin-4-inducing Factor from Schistosoma mansoni Eggs

Abstract

The eggs of the parasitic trematode Schistosoma mansoni are powerful inducers of a T helper type 2 (Th2) immune response and immunoglobulin E (IgE) production. S. mansoni egg extract (SmEA) stimulates human basophils to rapidly release large amounts of interleukin (IL)-4, the key promoter of a Th2 response. Here we show purification and sequence of the IL-4-inducing principle of S. mansoni eggs (IPSE). Stimulation studies with human basophils using SmEA fractions and natural and recombinant IPSE as well as neutralization and immunodepletion studies using antibodies to recombinant IPSE demonstrate that IPSE is the bioactive principle in SmEA leading to activation of basophils and to expression of IL-4 and IL-13. Regarding the mechanism of action, blot analysis showed that IPSE is an IgE-binding factor, suggesting that it becomes effective via crosslinking receptor-bound IgE on basophils. Immunohistology revealed that IPSE is enriched in and secreted from the subshell area of the schistosome egg. We conclude from these data that IPSE may be an important parasitederived component for skewing the immune response toward Th2.Infection with the parasitic trematode Schistosoma mansoni leads to a pronounced Th2 1 response and to elevated IgE production both in humans and in experimental animals. The definition of parasite-derived products capable of skewing the immune response toward Th2 would not only enhance our understanding of the defense mechanisms involved in helminth infections but may also lead to new insights into the pathogenesis of immediate-type hypersensitivity diseases such as asthma. However, in contrast to our increasing understanding of how pathogen-derived products can initiate Th1-type immune responses, there is so far little detailed knowledge about the nature of the parasite-derived molecule(s) and the underlying mechanisms that trigger and/or amplify a Th2-type reaction. In S. mansoni infection, a critical role in inducing a polarized Th2 response is played by the egg stage of the parasite (1), since a Th2 response and IgE production are only observed after egg deposition or following injection of schistosome eggs (2) or extracts thereof (3) into naive animals. By contrast, the initial larval (schistosomula) and adult worm stages rather induce a response skewed to Th1.It is now firmly established, both in vivo and in vitro, that the cytokine profile present during an immune reaction is an important element in directing the response to Th1 or Th2 and that IL-4 is the key cytokine responsible for biasing the immune reaction toward a Th2 phenotype (4 -7). In the human system, basophils are a prominent source of IL-4 and IL-13; these cells secrete large amounts of IL-4 and IL-13 in response to IgE-receptor cross-linking or activation by a combination of IL-3 and C5a (8, 9). Indeed, human basophils can be viewed as "innate Th2-type" effector cells, since IL-4 and IL-13 are expressed in a very restricted manner without production of any of the cytokines involved in Th1-type immune responses. We therefore ...

Cutting Edge: IPSE/alpha-1, a Glycoprotein fromSchistosoma mansoniEggs, Induces IgE-Dependent, Antigen-Independent IL-4 Production by Murine Basophils In Vivo

“…1B) and extended these observations to the single cell level. Soluble human IgE and IgG have been shown to bind IPSE/ alpha-1 Ag nonspecifically, thereby competing out Fc receptorbound Igs and suppressing the IL-4-inducing effect of IPSE/ alpha-1 (6). To test whether polyclonal murine Igs bind IPSE/ alpha-1, we preincubated SmEA, E. coli-IPSE, and Hp Ag with PBS or serum from Hp-infected mice before the addition of whole blood cells from Hp-infected 4get/KN2 mice (Fig.…”

“…Although IL-4 is known as a potent inducer of Th2 differentiation, the mechanisms by which S. mansoni eggs and their soluble Ags (SmEA) 4 induce IL-4 production and Th2 development are still elusive. Recently we identified a glycoprotein secreted by S. mansoni eggs, IPSE/alpha-1, as a factor triggering basophils from nonsensitized humans to release IL-4 in vitro when costimulated with IL-3 (5,6). However, it is not known whether this activity of IPSE/alpha-1 is limited to human basophils and whether basophils can be activated in vivo.…”

“…with OVA (100 g; Sigma-Aldrich) adsorbed to aluminum hydroxide (alum) and boosted 2 wk later. Crude Hp worm extracts (7), soluble SmEA, IPSE/alpha-1-depleted SmEA, and recombinant Escherichia coli-IPSE were prepared as described (6,10). Human embryonic kidney (HEK)-IPSE was purified from human 293 HEK cells transfected with the expression vector pMSII-IPSE.…”

Factors Associated with Resistance to Schistosoma mansoni Infection in an Endemic Area of Bahia, Brazil

“…15 The most abundant proteins in the egg, the interleukin-4-inducing principle from S. mansoni eggs (IPSE), by inducing IL-4 production is associated with a shift to a Th2 immune response. 16,17 In schistosomiasis-endemic areas, resistance to reinfection after specific chemotherapy has been correlated with a Th2 immune response, with the presence of specific IgE [18][19][20] and production of IL-4 and IL-5. 21 Conversely, susceptibility to infection has been correlated with high levels of specific IgG4.…”

Derived Products of Helminth in the Treatment of Inflammation, Allergic Reactions and Anaphylaxis

“…Alpha-1 is a dimer that cross-link IgE-FcRI complex on basophils, in an antigen-dependent manner, hence being named IL-4 inducing principle of schistosoma eggs (IPSE). It induces the degranulation of mouse and human basophils and releases of IL-4 release (Schramm et al, 2003(Schramm et al, , 2007, initiating Th2 differentiation. Omega-1 is a ribonuclease also secreted by schistosoma eggs which is necessary to egg transit into the host tissues (Fitzsimmons et al, 2005).…”